NM_001904.4:c.452G>A

CTNNB1 · NP_001895.1:p.(Arg151His) · NM_001904.4

GRCh37: chr3:41266655 G>A · GRCh38: chr3:41225164 G>A

Gene: CTNNB1 Transcript: NM_001904.4

Final call

PM2

Variant details

Gene

CTNNB1

Transcript

NM_001904.4

Protein

NP_001895.1:p.(Arg151His)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

CTNNB1 NM_001904.4:c.452G>A, p.(Arg151His) is present in gnomAD v4.1 at a total allele frequency of 0.000117726 (190/1613916) with a highest observed population frequency of 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 rarity threshold of 0.001 (0.1%), supporting rarity but not absence from population databases.

SpliceAI predicts a maximum delta score of 0.02, which is below the splice impact threshold of 0.2 and argues against a splice-disrupting effect.

ClinVar contains conflicting single-submitter classifications of likely benign and uncertain significance, so this assertion set does not provide decisive classification evidence.

In the absence of gene-specific criteria, robust case-level enrichment, segregation, de novo, or functional evidence, CTNNB1 p.(Arg151His) is classified as a variant of uncertain significance.

Final determination:

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Missense change NM_001904.4:c.452G>A results in p.(Arg151His) rather than a predicted loss-of-function variant, so PVS1 is not applicable.
PS1	Not assessed	No same-amino-acid pathogenic variant at this residue was documented in the reviewed workspace materials.
PS2	Not assessed	No de novo occurrence data with confirmed maternity and paternity were provided.
PS3	Not assessed	No validated functional assay results for CTNNB1 p.(Arg151His) were provided.
PS4	Not met	No case-control enrichment or multiple affected probands were established, and the PS4 literature screen did not identify supportive case evidence.	PMID:28492532
PM1	Not met	Cancer Hotspots did not identify residue Arg151 as a statistically significant hotspot, so PM1 is not supported by the assembled hotspot evidence.
PM2	Met	The variant is rare in population databases: gnomAD v4.1 total AF is 0.000117726 (190/1613916) and highest observed population AF is 0.000154237 in European non-Finnish individuals, both below the non-VCEP PM2 threshold of 0.001 (0.1%). gnomAD v2.1 also shows very low frequency (total AF 0.0000318573; highest population AF 0.000070466).	gnomad_v4 gnomad_v2
PM3	Not assessed	No data on occurrence in trans with a pathogenic variant were provided.
PM4	N/A	This is a missense substitution and not an in-frame deletion/insertion or stop-loss variant, so PM4 is not applicable.
PM5	Not assessed	No different pathogenic missense change at codon 151 was documented in the reviewed materials.
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was provided.
PP1	Not assessed	No segregation data were provided.
PP2	Not assessed	The reviewed workspace did not provide gene-level evidence sufficient to determine whether CTNNB1 has a low rate of benign missense variation and whether missense is a primary established disease mechanism for the relevant germline disorder.
PP3	Not met	SpliceAI shows a maximum delta score of 0.02, which is below the commonly used splice concern threshold of 0.2 and does not support splice disruption, and the available REVEL score of 0.466 is not sufficient on its own to establish deleterious computational evidence under a generic ACMG framework.	spliceai
PP4	Not assessed	No phenotype or family history information specific enough to assess PP4 was provided.
PP5	Not assessed	PP5 was not applied. ClinVar contains non-expert, conflicting single-submitter interpretations and this criterion is not used as decisive evidence here.	clinvar PMID:28492532
BA1	Not met	The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BA1 threshold of 0.01 (1%).	gnomad_v4
BS1	Not met	The highest observed gnomAD v4.1 population AF is 0.000154237 (0.01542%), which is below the non-VCEP BS1 threshold of 0.003 (0.3%).	gnomad_v4
BS2	Not assessed	No criterion-specific evidence for observation in healthy adults inconsistent with the expected penetrance or age of onset was provided.
BS3	Not assessed	No well-established functional studies demonstrating a benign effect were provided.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation were provided.
BP1	Not assessed	The reviewed workspace did not provide gene-level disease-mechanism evidence sufficient to support BP1 for CTNNB1 missense variation.
BP2	Not assessed	No phase information showing the variant in trans with a pathogenic variant or in cis with another variant was provided.
BP3	N/A	This is not an in-frame indel in a repetitive region, so BP3 is not applicable.
BP4	Not met	SpliceAI predicts no meaningful splice impact with a max delta score of 0.02, which is below 0.2, but the available generic ACMG evidence set does not provide sufficient calibrated benign missense prediction evidence to apply BP4 because the REVEL score of 0.466 is intermediate and no gene-specific computational framework is available.	spliceai
BP5	Not assessed	No alternate molecular diagnosis or established alternate cause for the phenotype was provided.
BP6	Not assessed	BP6 was not applied. ClinVar contains conflicting non-expert single-submitter assertions, which do not provide sufficiently strong benign evidence for this review.	clinvar
BP7	N/A	BP7 applies to synonymous or intronic variants with no predicted splice impact; this variant is missense and BP7 is not applicable.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.